Modified Release Tranexamic Acid Formulation

ABSTRACT

A modified release dosage form for the oral administration of tranexamic acid.

BACKGROUND OF THE INVENTION

The present invention relates to a stable formulation of tranexamic acid that provides improved taste profile and a therapeutic administration of tranexamic acid.

Tranexamic acid (trans-4-aminomethyl-cyclohexanecarboxylic acid) is an antifibrinolytic agent, which is used to prevent lysis or dissolution of fibrin clots. Its mechanism of action is as a competitive inhibitor of plasminogen activation, and as a noncompetitive inhibitor of plasmin; both plasminogen and plasmin are activators of fibrinolysis and active clot-lysing agents. Tranexamic acid assists in stabilizing fibrin clots, which maintains coagulation and assists in the control of bleeding.

Tranexamic acid is commercially available as 650 mg oral tablets under the trade name LYSTEDA® from Ferring Pharmaceuticals. Tranexamic acid is also available in intravenous form under the trade name CYKLOKAPRON® from Pharmacia and Upjohn.

Tranexamic acid is used to control excess bleeding, such as heavy bleeding during menstruation (menorrhagia). Women that suffer from menorrhagia are typically treated orally with 500 mg tranexamic acid tablets, which are administered three or four times daily. The total daily dosage ranges from 3 grams/day (two tablets every eight hours) to 6 grams/day (three tablets every six hours). Unfortunately, this treatment can cause adverse gastrointestinal reactions, including nausea, vomiting, diarrhea, and cramping. It is believed these gastrointestinal side effects are due to either large dosages of tranexamic acid and/or a rapid rate of release of tranexamic acid into the stomach following administration.

Additionally tranexamic acid has a bitter taste, and prior art tranexamic acid dosage forms are reported to be difficult to consume. This results in poor patient compliance.

A further disadvantage of such tranexamic acid-containing oral dosage forms is that they are unstable and tend to discolor upon aging. Prior art formulations are known which use cyclodextrin, chelating agents or a polycarboxylic acid derivative to prevent discoloration and improve stability. However, these approaches have several drawbacks, including lack of complete taste-masking and reduced stability of the tranexamic acid.

Other proposed attempts to solve the taste and stability problems have used enteric or delayed release coatings that delay the release of the tranexamic acid until after it has passed through the low pH environment of the stomach. These delayed release formulations were developed to improve the stability of the tranexamic acid dosage form, as well as improve patient compliance due to the poor taste profile of tranexamic acid. These techniques are described in U.S. Published Application Nos. 2005/0244495; 2005/0245614 and 2005/0025825. These delayed and modified release formulations employ dual layer coating techniques that involve the application of a separate functional coating and a seal coating layer, an operation which increases the length of the manufacturing process and the cost of the product. Further, enteric coated dosage forms can result in an unnecessarily long delay in the release of the tranexamic acid, thereby decreasing the effectiveness of the tranexamic acid.

The applicants have surprisingly discovered that the combination of a controlled release core and a coating system that avoids the need to use additional coating layers, or enteric coating agents on the tranexamic acid core tablet can produce stable, therapeutic and taste-masked solid dosage forms.

SUMMARY THE INVENTION

The present invention provides a novel dosage form of tranexamic acid that comprises or consists essentially of:

-   -   (a) a core comprising or consisting essentially of tranexamic         acid and a release controlling material; and     -   (b) a coating layer on said core that comprises or consists         essentially of a coating agent which is insoluble in water, but         soluble in aqueous media with a pH below 5 and preferably a pH         below 4.

The core may be in the form of pellets, mini tablets or compressed tablet cores. As used herein the term “pellets” refer to spherical or irregularly shaped particles having an average diameter of less than 1 mm. As used herein the terms “mini tablet” or “minitabs” are used interchangeably and refer to solid dosage forms that have a length and/or width that ranges from 1 mm or greater to about 5 mm. As used herein the term “tablet” is used in its conventional manner, and generally refers to a solid dosage form with a length and/or width greater than 5 mm. In the case of mini tablets and tablets the core is preferably a homogenous or uniform mixture of ingredients, i.e., not a multilayer core. The core may further comprise conventional tableting excipients such as binders, fillers, disintegrants, glidants, lubricants or mixtures thereof.

The coating layer is applied to and surrounds the core. In one embodiment of the present invention, the dosage forms employs only one functional coating layer and may optionally further comprise aesthetic coatings such as rapidly dissolving color coatings or wax polishing coatings. The aesthetic coatings, if employed, will not affect the release characteristics of the tranexamic acid from the dosage form. In addition to the coating agent, which is insoluble in water but soluble in aqueous media with a pH below 4, the coating layer, also referred to herein as a “functional coating,” may further comprise conventional processing aids such as binders, fillers, pigments, lubricants, plasticizers and mixtures thereof.

The coating agent, which is insoluble in water but soluble in aqueous media with a pH below 5, preferably a pH below 4, may be an amino methacrylate copolymer, preferably an aminoalkyl methacrylate copolymer. An example of a coating agent that is insoluble in water but soluble in aqueous media with a pH below 4, more preferably below 3, is commercially available from Degussa under the trade name EUDRAGIT® E.

Accordingly, it is a primary object of this invention to provide a solid oral pharmaceutical dosage formulation of tranexamic acid that is stable upon prolonged storage, is stable when administered to a patient and is capable of providing the desired therapeutic effect.

These and other objects of the invention will become apparent from a review of the present Specification.

DETAILED DESCRIPTION OF THE INVENTION

The tranexamic acid formulation of the invention may be prepared by mixing the tranexamic acid with the release controlling material, and optionally conventional processing aids, such as binders, fillers, disintegrants, glidants, lubricants, or mixtures thereof. The mixture may be directly compressed into a tablet or mini tablet core or granulated, either by wet or dry techniques to prepare pellet cores. The granules may also be used to prepare compressed tablet or mini tablet cores.

The tranexamic acid present in the core may comprise from about 40 to 95 wt %, preferably about 50 to 90 wt %, and most preferably about 55-85 wt % of the core.

Release controlling materials employed in the core may be hydrophilic and/or hydrophobic materials such as gums, cellulose ethers, acrylic resins, waxes, protein derived materials, or polyethylene oxides. Additional examples of release controlling materials that may be used in the present invention include hydrogenated castor oil, hydrogenated vegetable oils, natural and synthetic waxes such as beeswax, glycowax, castor wax, glycerol monostearate, glyceryl behenate, stearyl alcohol, alginates, carrageenan, carbomers, xanthan gum, locust bean gum, hydroxypropyl methylcelluloses, hydroxypropyl celluloses, hydroxyethyl celluloses, carboxymethycelluloses, polyethylene oxides and mixtures of thereof.

One embodiment of the present invention employs hydrophilic release controlling polymers as the release controlling material, and preferably water soluble release controlling polymers that swell and or gel when exposed to aqueous mediums. Some examples of the hydrophilic release controlling polymers include, but are not limited to hydroxypropyl methylcelluloses, hydroxypropyl celluloses, hydroxyethyl celluloses, carboxymethycelluloses, polyethylene oxides, and mixtures thereof. Representative examples of hydrophilic release controlling polymers are low viscosity hypromellose (such as METHOCEL® E 5 Premium, which is commercially available from Dow Chemical) and high molecular weight polyethylene oxides (such as POLYOX WSR 301, WSR 303 or WSR COAGULANT). The release controlling polymer is present in the present invention at approximately 1 to 25 wt %, preferably about 2 to 20 wt % and most preferably about 3 to 15 wt %.

Binders that may be employed in the core of the present invention are preferably a water soluble polymer of the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, copovidone (a/k/a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate) and mixtures thereof. A water soluble binder is preferred, which is applied from an organic medium such as ethanol at a level of from about 0.1 to 10 wt % and preferably from about 1 to 5 wt % of binder based on the total weight of the granulation. The preferred binder is copovidone. The binders typically exhibit a lower molecular weight than the release controlling materials.

Fillers that may be used in the core of the present invention include, but are not limited to sugars such as lactose, dextrose, sucrose, maltose, mannitol, microcrystalline cellulose and mixtures thereof. The filler may comprise from about 5 to 50 wt % and preferably about 10 to 30 wt % based on the total weight of the core.

Disintegrants that may be used in the core of the present invention include corn starch, potato starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof. The disintegrant may be present in the core from about 0.1 to 10 wt % and preferably about 0.5 to 5 wt % based on the total weight of the core.

The core may also comprise a flow aid or glidant. A glidant is an excipient that improves the flow characteristics of a compressible powder such as tablet ingredients or granules. Two of the most common glidants are colloidal silicon dioxide (CAB-O-SIL®) and Quso (also known as Phila Quartz). The amount of glidant that can be used in the present invention ranges from about 0.01 to 5 wt % and preferably about 0.1 to 2 wt % based on the total weight of the core. The preferred glidant is colloidal silicon dioxide.

Suitable lubricants possess anti-sticking or anti-tacking properties. Suitable lubricants used in preparing solid dosage forms may include talc, stearic acid, magnesium stearate, glyceryl monostearate, sodium stearyl fumarate, glyceryl behenate, hydrogenated oils, polyethylene glycols and sodium stearate. The amount of lubricant that can be used in the present invention ranges from about 0.01 to 10 wt % and preferably about 0.5 to 5 wt % based on the total weight of the core.

Once the core is prepared it is coated with a functional coating or a coating layer that comprises or consists essentially of a coating agent that is insoluble in water, but soluble in aqueous media with a pH below 5, preferably a pH below 4. This functional coating is applied by conventional coating techniques, such as pan coating or fluid bed coating using solution, suspension or dispersion of polymeric material in water or suitable organic solvents.

The functional coating should comprise about 10 to 75 wt %, preferably about 15 to about 50 wt %, based upon the total dry weight of the functional coating, of a coating agent that is insoluble in water, but soluble in aqueous media with a pH below 5, preferably a pH below 4. The coating agent may be an amino methacrylate copolymer, preferably an aminoalkyl methacrylate copolymer. An example of a coating agent that is insoluble in water, but soluble in aqueous media with a pH below 5, preferably below 4, and most preferably below 3 is EUDRAGIT® E. Additional examples are EUDRAGIT®E 100, EUDRAGIT®E PO and EUDRAGIT® 12.5. EUDRAGIT® E 100 is a poly(butyl methacrylate, (2-dimethyl aminoethyl)methacrylate, methyl methacrylate) copolymer. EUDRAGIT® E PO, which is also commercially available from Evonik Industries, is a cationic copolymer derived from poly(butyl methacrylate, (2-dimethyl aminoethyl)methacrylate, methyl methacrylate) and is soluble in gastric acid and in pH's up to 5.0. One g of EUDRAGRIT® E PO dissolves in 7 g methanol, ethanol, isopropyl alcohol, ethyl acetate, methylene chloride or 1 N hydrochloric acid to give clear to slightly cloudy solutions, and has a viscosity of approximately 3-6 mPa's. EUDRAGIT®E 12.5 is a commercially available coating solution containing EUDRAGOT®E 100 (12.5 w/w %) in a mixture of isopropyl alcohol and acetone. The pH dependent nature of the EUDRAGIT® E polymers allows the tranexamic dosage form to limit the release of the active agent until it has been deposited in the low pH gastric environment of the stomach. This allows for minimal release of tranexamic acid in the mouth, thereby overcoming the bitter taste. Further, because the functional coating does not completely obstruct the release of the tranexamic acid during the dosage form's period in the stomach, a therapeutic release of the active is still provided to the patient's stomach and upper part of the gastrointestinal tract.

In one embodiment of the present invention, the functional coating comprises about 1 to about 10 wt % based on the total weight of the dosage form, preferably about 2 to about 6 wt % based upon the total weight of the dosage form.

In the preparation of the tablets of the invention, various conventional, well-known solvents may be used to prepare the tablets and apply the functional coating to the tablets of the invention. In addition, various diluents, excipients, lubricants dyes, pigments, dispersants etc., which are disclosed in Remingtons' Pharmaceutical Sciences, 2000 Edition, may be used to optimize the formulations of the invention.

The functional coating can also contain additional coating agents that rapidly dissolve or disperse in aqueous media. One embodiment of the present invention employs a rapidly water soluble film forming agent such as low molecular weights hydroxypropyl methylcellulose, low molecular weight polyvinyl pyrrolidone, low molecular weight polyvinyl alcohols or mixtures thereof. As used herein the term “rapidly water soluble” means films prepared from the material will dissolve or disperse within 10 minutes when placed in 900 ml of water. Some of the film forming agents useful for incorporation into the functional coating of the present invention are commercially available from Colorcon under the trade name OPADRY®, such as OPADRY® clear, OPADRY® white or OPADRY® yellow. The film former if incorporated into the functional coating of the present invention should comprise about 20% to about 80%, preferably about 45% to about 75% based upon the total dry weight of the functional coating.

The functional coating may also contain plasticizers. Plasticizers that may be used include any of those known to those skilled in the art, including but not limited to, acetyltributyl citrate, triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyltriethyl citrate, glycerin sorbitol, diethyloxalate, diethylmatate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylphthalate, dibutylsebacate, triethyl citrate, tributylcitrate, glyceroltributyrate, polyethylene glycol, propylene glycol and mixtures thereof. The amount of plasticizer employed in the functional coating can range from about 0.1 to about 20%, and most preferably from about 1 to about 10% based on the total dry weight of the functional coating.

The functional coating may also include an inert processing aid or an anti-sticking agent such as those selected from the group consisting of talc, colloidal silica dioxide, magnesium stearate, magnesium silicate, glyceryl monostearates, calcium stearate or steric acid. If an anti-sticking agent is employed in the functional coating, the amount employed should range from about 0.1 to about 30%, and most preferably about 1 to 10% based on the total dry weight of the functional coating.

One embodiment of the present invention requires the core to be a homogeneous or unitary core that is compressed into a mini tablet or tablet. The compressed core may be formed by mixing the core ingredients and directly compressing the mixture. The core may also be formed by preparing a wet or dry granulation of the ingredients and compressing the granules into the core structure.

In one embodiment, the core is formed by wet granulating the core ingredients with water, isopropyl alcohol, acetone, ethanol or the like. The wet granules are dried and sized then blended with addition ingredients, i.e., extra-granular excipients, such as binders, fillers, disintegrants, glidants, lubricants and mixtures thereof, and the blend is compressed into the homogeneous or unitary cores.

Embodiments of the present invention may comprise the ingredients as outlined the following table:

Ingredient Preferred (wt %) Most Preferred (wt %) Compressed matrix core¹ Tranexamic acid 50-90%  55-85% Release controlling material 2-20%  3-15% Binder 0.1-10%   1-5% Filler 5-50% 10-30% Glidant 0.01-5%    0.1-2%   Disintegrant 0.1-10%   0.5-5%   Lubricant 0-10% 0-5% Functional coating² Coating agent that is insoluble 5-50% 15-30% in water but soluble in aqueous media with a pH below 5 Film former 25-80%  45-75% Plasticizer 0.1-20%    1-10% Anti-sticking agent 1-30%  5-15% ¹Wt % based on the total weight of the core. ²Wt % based on the total dry weight of the coating.

The dissolution profile of the dosage form prepared according to the present invention should exhibit the following dissolution profile when tested in a USP type 2 (paddle) apparatus at 50 rpms in 900 ml of water at 37° C.

DRUG RELEASED Time (minutes) Preferred Most Preferred 15 0-20%  0-10% 30 0-40% 10-20% 45 5-50% 10-30% 60 *NLT 10% NLT 15% 90 NLT 15% NLT 25% 120 NLT 25% NLT 30% 150 NLT 30% NLT 35% *NLT = Not Less Than

The dissolution profile of the dosage form prepared according to the present invention should exhibit the following dissolution profile when tested in a USP type 2 (paddle) apparatus at 50 rpms in 900 ml of 0.1 N HCl at 37° C.

DRUG RELEASED Time (minutes) Preferred Most Preferred 15 10-50% 25-45% 30 40-95% 60-85% 45 50-99% 80-99% 60 NLT 70% NLT 80% 90 NLT 80% NLT 95% 120 NLT 85% NLT 90% 150 NLT 90% NLT 95%

EXAMPLES

The following are provided by way of example only and are in no means intended to be limiting.

Example 1 Granulation

The formulation for making the tranexamic acid granulation has the following composition:

tranexamic acid, USP 650.0 mg/tab microcrystalline cellulose (AVICEL ® PH101) 154.3 mg/tab glyceryl behenate NF, (COMPRITOL ® 888 ATO) 8.286 mg/tab hypromellose, 2910 USP (METHOCEL ® E5 Premium)  65.0 mg/tab copovidone (PLASDONE ® S 630) 27.86 mg/tab

Copovidone is dissolved in a sufficient amount of ethanol to allow it to completely dissolve. Next, the tranexamic acid, microcrystalline cellulose, glyceryl behenate and hypromellose are passed through a comil and blended in a V-blender for approximately 15 minutes. The blend is then loaded into a high shear granulator and mixed for approximately 2 minutes. The solution of copovidone and ethanol is then sprayed onto the mixed blend in the granulator until the granulation is complete. The granulation is then dried in an oven at 60∓5° C. until the loss on drying (LOD) is less than 1 .2%. The dried granules are passed through a comil.

Blending

The comilled granulate is then blended with the following extra-granular ingredients:

copovidone (PLASDONE S 630) 4.741 mg/tab crospovidone, NE (POLYPLASDONEe XL-10) 19.49 mg/tab lactose monohydrate, NF Modified Spray Dried 24.42 mg/tab (Lactose 316 Fastflo) colloidal silicon dioxide, NF (Cab-O-Sil M5P) 4.741 mg/tab magnesium stearate, NF 9.481 mg/tab

The copovidone, crospovidone, lactose monohydrate and colloidal silicon dioxide are passed through a comil. The comilled granules and comilled additional excipients are loaded into a V-blender and blended for approximately 15 minutes. Magnesium stearate is then screened through a 30 mesh screen and added into the V-blender with the blended mixture for approximately 5 minutes.

Tabletting

The blended granulation is tabletted into tablet cores containing 650 mg of tranexamic acid using a high speed rotary tablet press to form oval shaped tablets. The target weight is 968.6 mg/tab and the target hardness is 13-20 Kp.

Coating

A functional coating of the following formulation is then applied to the compressed tablet cores:

tranexamic acid tablet cores 968.3 mg/tab  (prepared above) OPADRY Clear*, YS-1-7006 18.54 mg/tab  EUDRAGIT ® E PO 6.18 mg/tab triethyl citrate, NF 1.24 mg/tab talc USP (Imperial Talc 500) 3.09 mg/tab *OPADRY Clear is believed to contain hypromellose and polyethylene glycol

Triethyl citrate is added to acetone and isopropyl alcohol and allowed to homogenize. Next, talc is added to the solution and allowed to homogenize. A second solution is formed comprising acetone, isopropyl alcohol and purified water to which EUDRAGIT® E PO and OPADRY® Clear are sequentially dissolved. The two solutions are combined and stirred. The coating solution is then sprayed onto the compressed tablet cores until a total weight gain of 29.05 mg/tablet (3% weight gain) is achieved.

The resulting tablets were tested in two separate solutions containing water and simulated gastric fluid (SCE, pH 1.2, 0.1 N HCl), according to the procedure described in United States Pharmacopoeia 25, using Apparatus II, paddle@50 rpm in 900 ml. The mean results of three (3) in vitro tests were as follows:

In water:

TIME (in minutes) % RELEASED 0 0 15 5 30 10 45 15 60 18 90 27 120 35 150 41

In SGF:

TIME (in minutes) % RELEASED 0 0 15 37 30 73 45 94 60 97 90 97 120 97 150 98

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations, which is not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms “comprising,” “consisting essentially Of” and “consisting of” may be replaced with either of the other two terms. The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims. 

1-24. (canceled)
 25. A modified release dosage form consisting essentially of: (A) a compressed matrix core which comprises: (i) tranexamic acid; (ii) a release controlling material; and (iii) a tableting excipient selected from the group consisting of binders, fillers, disintegrants, glidants, lubricants or mixtures thereof; (B) a functional coating applied to and surrounding the compressed matrix core which comprises: (i) a coating agent which is insoluble in water but soluble in aqueous media with a pH below 4; and (ii) a processing aid selected from the group consisting of a binder, filler, pigment, lubricant, plasticizer and mixtures thereof; and (C) optionally an aesthetic coating.
 26. The modified release dosage form as defined in claim 25 wherein the dosage form is a tablet or mini tablet.
 27. The modified release dosage form as defined in claim 25 wherein the coating agent which is insoluble in water but soluble in aqueous media with a pH below 4 is an aminoalkyl methacrylate copolymer.
 28. The modified release dosage form as defined in claim 25 wherein the compressed matrix core has a hardness of 13-20 kp.
 29. A modified release tablet consisting essentially of: (A) a compressed matrix core which comprises: (i) tranexamic acid; (ii) a release controlling material; and (iii) a tableting excipient selected from the group consisting of binders, fillers, disintegrants, glidants, lubricants or mixtures thereof; (B) a functional coating applied to and surrounding the compressed matrix core which comprises: (i) an aminoalkyl methacrylate copolymer that is insoluble in water but soluble in aqueous media with a pH below 4; and (ii) a processing aid selected from the group consisting of a binder, filler, pigment, lubricant, plasticizer and mixtures thereof; and (C) optionally an aesthetic coating, wherein the compressed matrix core has a hardness of 13-20 kp. 